Diabetes Ther (2014) 5:141

DOI 10.1007/s13300-014-0061-3

REVIEW

Comparative Effectiveness of Dipeptidylpeptidase-4 Inhibitors

in Type 2 Diabetes: A Systematic Review and Mixed Treatment
Comparison
Paul Craddy

Hannah-Jayne Palin

K. Ian Johnson

To view enhanced content go to www.diabetestherapy-open.com Received:

December 20, 2013 / Published online: March 25, 2014
The Author(s) 2014. This article is published with open access at Springerlink.com
H.-J. Palin K. I. Johnson
(&)
McCann
Complete
Objective: To compare the safety and efficacy Medical,
of the dipeptidylpeptidase-4 (DPP-4) inhibitors Macclesfield,
UK e-mail:
in patients with type 2 diabetes and inadequateian.johnson@co
mplete-grp.com

ABSTRACT

glycemic control.

Design: Systematic review of randomized

controlled trials (RCTs), health economic
evaluation studies, systematic reviews, and
meta-analyses, followed by primary Bayesian
mixed treatment comparison meta-analyses
(MTCs), and secondary frequentist directcomparison meta-analyses using a randomeffects model. Outcomes were reported as
weighted mean change from baseline, or odds
ratio (OR) with 95% credible interval.
Data sources: MEDLINE, MEDLINE InProcess, EMBASE, and BIOSIS via Dialog
ProQuest; Cochrane Central Register of
Controlled Trials
Electronic supplementary material The online version
of this article (doi: 10.1007/s13300-014-0061-3)
contains supplementary material, which is available to
authorized users.

P. Craddy
Takeda Pharmaceuticals International GmbH,
Zurich, Switzerland

and Cochrane Database

of Systematic Reviews
via
EBSCO;
four
diabetes
and
two
technical
congress
abstracts; and health
technology assessment
organization websites.
Eligibility
criteria:
Patients with type 2
diabetes and inadequate
glycemic
control
receiving
any
pharmacological antidiabetic treatment.
Data extraction and
analysis: Title/abstracts
were reviewed for
eligibility, followed by
full-text review of
publications remaining
after first pass. A threeperson team filtered
articles
and
an
independent reviewer
checked a random
selection (10%) of
filtered articles. Data
extraction and quality
assessment of studies

were also independently reviewed. Five DPP-4

inhibitors (alogliptin, linagliptin, saxagliptin, Results: The review
sitagliptin, and vildagliptin) were compared via identified
6,601
meta-analysis (where data were available) asarticles;
163
met
monotherapy, dual therapy (plus metformin,inclusion criteria and 85
sulfonylurea, pioglitazone, or insulin), and publications from 83
triple therapy (plus metformin/sulfonylurea). RCTs
contained

sufficient or appropriate
data for analysis. MTCs
demonstrated
no
differences
between
DPP-4 inhibitors in
mean change from
baseline in

Diabetes Ther (2014) 5:141

clinical
trial
was
identified in the Scheen
glycosylated hemoglobin (HbA1c) or body weight, or the with SUs, and weight
proportions of patients achieving HbA1c \7% orneutrality, compared with
experiencing a hypoglycemic event, apart from in patients the weight gain that is
generally associated with
on alogliptin plus metformin, who achieved HbA1c
and
\7% more frequently than those treated with saxagliptin SUs
plus metformin [OR 6.41 (95% CI 3.1511.98) versus thiazolidinediones [ 2].
2.17 (95% CI 1.562.95)].
Previous
indirect
Conclusions: This systematic review and MTC showed comparisons of the DPP-4
in
several
similar efficacy and safety for DPP-4 inhibitors as inhibitors
treatment for type 2 diabetes, either as monotherapy or published meta-analyses [
combination therapy.
4 8] have reported little
or no difference between
Keywords: Alogliptin; DPP-4 inhibitor; Glycosylated them with regard to
hemoglobin; Linagliptin; Mixed treatment comparison; efficacy,
both
as
Saxagliptin; Sitagliptin; Type 2 diabetes mellitus; monotherapy and
in
Vildagliptin
combination with other
anti-diabetic drugs, and

review [ 2]. This 18-week

trial
compared
the
efficacy of saxagliptin 5
mg and sitagliptin 100 mg
in
combination
with
metformin in patients
with type 2 diabetes
inadequately controlled
with metformin alone [
10]. The between-group
adjusted mean change
from baseline in HbA1c
demonstrated
no
difference
between
saxagliptin and sitagliptin.

INTRODUCTION

the overall safety profile [

2]. However, there are
Dipeptidylpeptidase-4 (DPP-4) inhibitors have aseveral
important
mechanism of action that is distinct from other oral differences between the
glucose-lowering agents [ 1]. The DPP-4 inhibitor class of DPP-4 inhibitors with
oral anti-diabetic agents selectively inhibits the DPP-4 regard to their absorption,
enzyme that rapidly degrades two major incretin distribution, metabolism,
hormones, glucagon-like peptide-1 (GLP-1) and glucose- and elimination, as well
as potency and duration
dependent insulinotropic polypeptide [ 2].
of action [ 2]. These
may,
Scheen [ 2] reviewed DPP-4 inhibitors in 2011,differences
potentially,
be
clinically
analyzing the similarities and differences among members
of the DPP-4 inhibitor class of oral anti-diabetic agents,relevant, particularly in
including their efficacy and safety profiles as patients with renal or
monotherapy or in combination with metformin, a hepatic impairment, and
sulfonylurea (SU) and/or a thiazolidinedione, and insulin.in patients receiving
therapy,
The review demonstrated that, although DDP-4 inhibitors combination
produce a similar reduction in glycosylated hemoglobin especially those with
cardiovascular
disease
(HbA1c) levels compared with other existing classes of
oral glucose-lowering agents, DPP-4 inhibitors offer taking multiple drugs [ 2,
9]. However, there is a
several clinical advantages [ 3]. These include negligible
lack of head-to-head
risk of hypoglycemia, much lower than that observed
clinical trials comparing
DPP-4 inhibitors: a single

Esposito et al. [ 5]
conducted a systematic
review and meta-analysis
of indirect comparisons of
the DPP-4 inhibitors
vildagliptin, sitagliptin,
saxagliptin, and alogliptin
in 2011. The primary
outcome of the analysis
was the proportion of
patients achieving an
HbA1c level \7%, with the
absolute change from
baseline
in
HbA1c,
proportion of patients
with
hypoglycemic
events, and change from
baseline in body weight
as secondary outcomes.
The systematic review of
published
literature
identified no randomized
controlled trials (RCTs)
with the

Diabetes Ther (2014) 5:141

DPP-4 inhibitor linagliptin and was limited to trials

published up until September 2010. Separate metaanalyses were conducted for each DPP-4 inhibitor
compared with placebo and other anti-diabetic agents
(including
metformin,
SUs,
pioglitazone,
and
rosiglitazone) for each of the outcomes.
We have conducted a similar review of DPP-4
inhibitors; as monotherapy compared with placebo, and as
dual or triple therapy (where data were available)
compared with metformin, SUs, metformin plus SU,
pioglitazone, and insulin. Included studies were identified
for all pharmacologic therapies for type 2 diabetes.
Following this wider review, we extracted data from
RCTs in patients treated with a DPP-4 inhibitor and
conducted mixed treatment comparison meta-analyses
(MTCs) to demonstrate the relative treatment effects of
each DPP-4 inhibitor compared with a common
comparator, assessing the same four outcomes as reported

safety of DPP-4 inhibitors

compared to other oral
and
injectable
antidiabetic pharmacologic
interventions, including
insulin, in the treatment
of patients with type 2
diabetes
who
were
receiving monotherapy,
dual, or triple therapy.
The research question and
eligibility criteria for this
systematic
review
conformed
to
the
following
PICOS
description [ 11]; studies
meeting these criteria
were
considered
for
inclusion:

by Esposito et al. [ 5].

1 Population: patients of
The aim of the MTCs was to test the hypothesis of no
difference between the DPP-4 inhibitors with regard to
glycemic control [mean HbA1c change from baseline,
proportion of patients achieving target HbA 1c (\7%)],
number of patients with hypoglycemic events, and mean
change from baseline in body weight.

any age or sex with

type 2 diabetes and
insufficient glycemic
control
(including
first-, second-, and
third-line
treatment
regimens).

2 Intervention:

METHODS
The analysis in this article is based on previously
conducted studies and does not involve any new studies of
human or animal subjects performed by any of the
authors.

Systematic Literature Search

We conducted a systematic review of published literature
to assess the comparative efficacy and

any
DPP-4
inhibitor
(alogliptin, linagliptin,
saxagliptin, sitagliptin,
and
vildagliptin),
GLP-1 or sodiumglucose co-transporter
2
inhibitors,
or
pioglitazone used in
the treatment of type 2
diabetes
(as
monotherapy, dual or
triple therapy).

3 Comparator:

any

pharmacologic

anti-diabetic

treatment, placebo, or standard of care for diabetes.

4 Outcome(s): HbA1c (mean change from

baseline and proportion of patients achieving HbA1c
target), fasting plasma glucose (FPG), low-density
lipoprotein cholesterol, high-density lipoprotein
cholesterol, triglycerides, body weight, and
hypoglycemia and serious adverse events.

5 Study type(s): blinded and open-label RCTs, health

economic evaluation
studies,
systematic
reviews, and metaanalyses.
Observational studies
and
retrospective
analyses were not
included.
Please note that this
article
focuses
on

analyses
inhibitors
following

of
DPP-4
for
the
outcomes:

mean change in HbA1c

from baseline, proportion
of patients achieving
HbA1c \7%, mean change
from baseline in body
weight, and number of
patients experiencing a
hypoglycemic event.

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